Evidence of serologic activity in chronic hepatitis B after surface antigen (HBsAg) seroclearance documented by conventional HBsAg assay

Background

Possible serologic activity after hepatitis B surface antigen (HBsAg) seroclearance documented by conventional assays in chronic hepatitis B (CHB) has not been thoroughly investigated.

Methods

We determined the levels of serum hepatitis B virus (HBV) DNA, hepatitis B core-related antigen (HBcrAg), and linearized HBsAg (CLEIA prototype) in 329 CHB patients (72.0% male) after HBsAg seroclearance was documented by a conventional HBsAg assay.

Results

The median interval between presentation and HBsAg seroclearance was 69.4 months. The median age at HBsAg seroclearance was 50 years. Assays for serum HBV DNA, HBcrAg, and linearized HBsAg were performed at a median time interval of 11.2 months after HBsAg loss. Linearized HBsAg and HBcrAg were detectable in 85 (25.8%) and 69 (21%) patients, respectively, and one or both serologic markers were detectable in 133 patients (40.4%). Serum HBV DNA was detectable in only 7 patients (2.1%). There was no correlation between linearized HBsAg and HBcrAg levels (r = 0.095, p = 0.924). The incidences of detectable linearized HBsAg and HBcrAg did not differ between patient samples taken at 6–12 and >12 months after HBsAg seroclearance (p = 0.146 and 0.079, respectively). Among patients with detectable serologic markers, median levels of linearized HBsAg (p = 0.581) and HBcrAg (p = 0.951) did not significantly change with time after HBsAg seroclearance.

Conclusion

Using novel HBcrAg and linearized HBsAg assays, viral serologic activity after HBsAg seroclearance was demonstrated in more than 40% of CHB patients. These tests have potential applications in diagnosing and prognosticating CHB patients with HBsAg seroclearance.     

Serum hepatitis B surface antigen (HBsAg) kinetics in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B

Background

We investigated the differences in HBsAg kinetics at different levels of viremia in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB).

Methods

We compared HBsAg levels among HBeAg-negative CHB patients with persistently undetectable HBV DNA (≤20 IU/mL; Group A, n = 100), HBV DNA 20–2,000 IU/mL (Group B, n = 100), and HBV DNA >2,000 IU/mL (Group C, n = 100). HBsAg and HBV DNA levels were measured at three consecutive time points during follow-up (median 21.4 months).

Results

Median HBsAg levels were significantly lower in Group A than in Groups B and C at all time points (p < 0.001). HBV DNA and HBsAg levels were weakly correlated (r = 0.180 and 0.151 for Groups B and C, respectively). Among patients with HBsAg <100 IU/mL, Group A patients had the greatest median serum HBsAg reduction (0.341 log IU/mL/year; Group B, 0.122 log IU/mL/year; Group C, 0.057 log IU/mL/year; p = 0.002). Among Group A patients with HBsAg <100 IU/mL, baseline HBsAg achieved an AUROC of 0.876 in predicting >1 log annual HBsAg reduction; 10–100 IU/mL HBsAg was the optimal level for prediction (sensitivity 90 %; specificity 74.6 %). Serum HBsAg/HBV DNA ratios were significantly higher in Group B than in Groups A and C (p < 0.05).

Conclusions

HBV DNA and HBsAg were weakly correlated. Only patients with undetectable HBV DNA showed decline in HBsAg levels during follow-up. The greatest reduction in HBsAg levels occurred in patients with baseline HBsAg <100 IU/mL.     

Combining the HBsAg decline and HBV DNA levels predicts clinical outcomes in patients with spontaneous HBeAg seroconversion

Purpose

The aim was to investigate whether the quantitation of the hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA levels can predict HBV reactivation and advanced liver disease after spontaneous hepatitis B e antigen (HBeAg) seroconversion.

Methods

A total of 121 patients who experienced spontaneous HBeAg seroconversion were included in this longitudinal study. Serial HBsAg and HBV DNA levels were measured before and after HBeAg seroconversion.

Results

Of the 121 patients, 32 experienced HBV reactivation and six achieved an HBsAg loss after HBeAg seroconversion during the follow-up period. The decline in the HBsAg level was considerably more pronounced in patients without HBV reactivation when compared to those with HBV reactivation (p = 0.016). Multivariate analysis revealed that the age of >40 years at HBeAg seroconversion, male sex, and HBsAg decline, and HBV DNA levels at month 12 after HBeAg seroconversion were independent factors for the development of HBeAg-negative hepatitis. All the six patients who achieved HBsAg loss had HBsAg level of <1,000 IU/mL at month 12 after HBeAg seroconversion (p < 0.001). The risk of HBeAg-negative hepatitis, cirrhosis, and HCC was substantially increased in patients who had a combination of both, i.e., no decline in the HBsAg level and HBV DNA level of >10⁴ copies/mL at month 12 after HBeAg seroconversion.

Conclusions

Combining HBsAg reduction and HBV DNA levels at month 12 after HBeAg seroconversion was a useful marker to predict clinical outcomes in spontaneous HBeAg seroconverters. HBsAg level of <1,000 IU/mL at month 12 after HBeAg seroconversion could predict the HBsAg loss after HBeAg seroconversion.     

Prevalence and time course of hepatitis B virus infection in patients with systemic lupus erythematosus under immunosuppressive therapy

Objective

To clarify the prevalence and time course of hepatitis B virus (HBV) infection in patients with systemic lupus erythematosus under immunosuppressive therapy.

Methods

We performed serological examination of 248 lupus patients to determine the presence of HBV, including hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc). Serum HBV DNA levels were measured in HBsAg-positive patients or resolved HBV carriers (HBsAg-negative, anti-HBs-positive, and/or anti-HBc-positive). If possible, we repeatedly performed examination of markers of HBV infection in resolved carriers.

Results

Two (0.8 %) patients were positive for HBsAg. Among 41 (16.5 %) patients who were considered as resolved HBV carriers, 1 (2.4 %) showed serum HBV DNA, which indicated occult HBV infection. The mean age and positive rate of anti-double stranded DNA antibody were significantly higher in resolved carriers than in anti-HBs- and anti-HBc-negative patients. Repeated examination showed that the anti-HBs and anti-HBc titer decreased below the threshold in 4 resolved carriers.

Conclusions

The prevalence of resolved HBV carriers in Japanese lupus patients was 16.5 %. Among them, occult HBV infection and decrease in anti-HBs and anti-HBc titer were observed. These findings indicated that all lupus patients should undergo serological examination for HBV before treatment. If patients have already been treated, we must carefully monitor their liver function, even when all HBV markers are negative.     

Occult hepatitis B virus infection as a cause of posttransfusion hepatitis in patients with cancers

Background

Prevalence of hepatitis B virus (HBV) infection is increased in patients of cancer with increased mortality. Multiple transfusions of blood and blood-related products are a potential source.

Aims

This study aims to assess the incidence of hepatitis B surface antigen (HBsAg) seroconversion in cancer patients receiving transfusion of blood or blood-related products and identify possible reasons for infection in these patients.

Material and Methods

Patients of cancer receiving blood products, who were HBsAg-, anti-hepatitis B core (HBc)-, and HBV DNA-negative prior to transfusion, were tested for HBsAg by ELISA at 6, 12, and 24 weeks after the last transfusion. Blood donors were screened for HBsAg by ELISA.

Results

Twenty of 3,600 (0.56 %) blood donors tested positive for HBsAg and were rejected. Nine of 150 (6 %) cancer patients became HBsAg-positive posttransfusion which included seven patients who presented with acute hepatitis B and other two patients who remained HBsAg-positive without hepatitis. In 6/9 (66.6 %) patients, HBsAg positivity was related to blood transfusion as their corresponding blood donors on retesting the stored samples were positive for anti-HBc antibody and HBV DNA. In other three patients, the cause of their HBsAg positivity could not be ascertained.

Conclusion

Occult HBV infection in blood donors is a potential source of posttransfusion HBV infection in recipients. Anti-HBc antibody and HBV DNA should be tested in blood donors especially when blood is given to cancer patients receiving chemotherapy.     

Seroclearance rate of hepatitis B surface antigen in 2,112 patients with chronic hepatitis in Japan during long-term follow-up

Background

Rate of hepatitis B surface antigen (HBsAg) seroclearance was determined in 2,112 Japanese patients with chronic hepatitis B who were followed up for at least 15 years.

Methods

Patients had a median age of 37 years and included 1,431 (67.8 %) men. Median values were AST/ALT, 43/62 IU/L; platelet counts, 182 × 10³/mm³; HBsAg, 3,400 IU/mL; and hepatitis B virus (HBV) DNA, 6.2 log copies/mL. Factors influencing HBsAg seroclearance were evaluated by the Cox proportional model and annual rate of HBsAg seroclearance by the Kaplan–Meier life table method.

Results

The overall annual rate of HBsAg seroclearance was 1.75 % in 2,112 patients; it was 1.65 % in 1,130 untreated and 2.05 % in 982 treated patients (p = 0.289). In untreated patients, seroclearance was influenced by age, no HBV infections in third-degree or closer relatives, and HBsAg levels in univariate analysis. Seroclearance was influenced by a median age ≥50 years [relative risk (RR) 1.61 (p = 0.018)] and HBsAg ≤2,000 IU/mL [RR 1.77 (p = 0.014)] in multivariate analysis. In treated patients, age, male gender, no HBV infections in third-degree or closer relatives, interferon therapy, chronic hepatitis, high AST and γ-GTP levels, low platelet counts, hepatitis B e antigen (HBeAg)-negative status, low HBsAg levels and the wild-type precore sequence significantly influenced HBsAg seroclearance. In multivariate analysis, no family history [RR 2.22 (p = 0.006)], interferon treatment [RR 3.15 (p < 0.001)], and HBeAg-negative status [RR 3.75 (p < 0.001)] significantly influenced HBsAg seroclearance.

Conclusions

In this retrospective cohort study, the annual rate of HBsAg seroclearance was 1.65 % in untreated patients and 2.05 % in treated patients.     

Tenofovir rescue therapy in chronic hepatitis B patients who failed previous nucleoside analogue treatment

Background

Tenofovir (TDF) is considered as the first line therapy for chronic hepatitis B. This study presents the results of TDF monotherapy in patients who failed previous nucleoside analogue treatment.

Methods

The study included 29 patients treated with TDF 245 mg once daily for 18 months after lamivudine monotherapy (LAM arm: n = 15) or sequential therapy with lamivudine and entecavir (LAM → ETV arm: n = 14). The previous antiviral therapy was discontinued due to lack of efficacy. All patients had HBV DNA between 2.1 and 8.23 log₁₀ IU/ml and 15 were HBeAg-positive, while 45 % of patients had increased ALT activity. Undetectable HBV DNA (<20 IU/ml) at months 3, 6, 12 and 18 was the primary endpoint in the study, while HBeAg/HBsAg loss/seroconversion and ALT normalisation were secondary endpoints.

Results

Primary nonresponse to TDF was not observed. HBV DNA was undetectable in 80, 80, 80 and 93 % in LAM arm and 50, 71, 86 and 86 % in LAM → ETV arm patients, at 3, 6, 12 and 18 months of TDF therapy, respectively. One patient achieved anti-HBeAg seroconversion. 86.5 % of patients had normal ALT activity at the end of the study. The baseline HBV DNA load, HBeAg status and the length of the duration of TDF therapy appeared significantly associated with the response to the therapy. HBV DNA clearance occurred faster in HBeAg-negative patients than in those positive for HBeAg.

Conclusions

TDF is an effective antiviral medication in patients with previous exposure to LAM or LAM and ETV. Final proportion of patients who achieved undetectable HBV DNA and had normal ALT activity in both arms, was similar.

     

Therapeutic potential of a combined hepatitis B virus surface and core antigen vaccine in patients with chronic hepatitis B

Purpose

The safety and clinical efficacy of a vaccine containing both hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) (HBsAg/HBcAg) were evaluated in patients with chronic hepatitis B (CHB).

Methods

Eighteen patients with CHB were administered a vaccine containing 100 μg of HBsAg and 100 μg of HBcAg. The vaccine was administered ten times at 2-weekly intervals, the first five times via the nasal route only and the subsequent five times via both nasal and subcutaneous routes. The safety and efficacy of this therapeutic approach were assessed by periodic assessment of the patients’ general condition, viral kinetics, and biochemical parameters during treatment and 24 and 48 weeks after therapy. The production of cytokines by peripheral blood mononuclear cells (PBMC) and antigen-pulsed dendritic cells (DC) was evaluated to assess the immunomodulatory effects of the HBsAg/HBcAg vaccine in CHB patients.

Results

The HBsAg/HBcAg vaccine was safe in all patients. No flare of HBV DNA or alanine aminotransferase (ALT) was recorded in any patient. Sustained HBV DNA negativity and persistently normalized ALT were detected in 9 (50 %) and 18 (100 %) patients with CHB, respectively. PBMC and HBsAg/HBcAg-pulsed DCs from HBsAg/HBcAg-vaccinated CHB patients produced significantly higher levels of various cytokines [interleukin 1β (IL-1β), IL-6, IL-8, IL-12, and tumor necrosis factor α (TNF-α)] than those from control unvaccinated CHB patients (p < 0.05) after stimulation with HBsAg/HBcAg in vitro.

Conclusion

HBsAg/HBcAg vaccine seems a safe and efficient therapeutic approach for patients with CHB.     

HBsAg, HBeAg and HBV DNA level changes and precore/basal core promoter mutations in the natural history of chronic hepatitis B in Indonesian patients

Introduction

Chronic hepatitis B (CHB) is a state of complex interactions between the hepatitis B virus (HBV) and host. We studied the changes in hepatitis B surface antigen (HBsAg), hepatitis B ‘e’ antigen (HBeAg) and HBV DNA levels, considering the implications of HBV genotype, basal core promoter (BCP) A1762T/G1764A and precore G1896A mutations in CHB.

Methods

One hundred fifty-two treatment-naïve CHB patients were classified into immune-tolerant (IT), immune-clearance (IC), low/non-replicative (LR) and ‘e’-negative hepatitis B (ENH) phases, based on HBeAg status, HBV DNA and ALT levels. HBV DNA was detected and quantified by polymerase chain reaction, then analyzed by sequencing. HBsAg and HBeAg levels were measured serologically.

Results

HBsAg and HBV DNA levels varied between CHB phases, with HBsAg highest in IT and lowest in LR, and HBV DNA high in IT and IC, and lowest in LR. Both markers increased in ENH. Correlation between HBsAg and HBV DNA was significant in IT and IC, modest in ENH, but missing in LR. HBeAg and HBV DNA levels were dissociated in HBeAg-positive patients. Genotypes B and C were similarly distributed, with precore mutations higher in HBeAg-negative patients and BCP mutations comparable in all phases. Temporal association between HBeAg seroconversion and an increase of BCP/precore mutations was observed.

Conclusion

HBsAg and HBV DNA levels were high and correlated in early CHB phases and dissociated after HBeAg seroconversion, indicating different controls affecting HBV replication and HBsAg production. Selection of BCP/precore mutants may affect disease course and explain the HBeAg–HBV DNA dissociation, a precaution for clinical application of quantitative HBeAg.     

Changes in the serum level of hepatitis B virus (HBV) surface antigen over the natural course of HBV infection

Background

Despite its status as a potential biomarker of hepatitis B virus (HBV) response to interferon treatment, the changes in hepatitis B surface antigen (HBsAg) levels over the natural course of HBV carriers have not been analyzed sufficiently.

Methods

A total of 101 HBV carriers were followed prospectively from 1999 to 2009. HBsAg level was measured yearly during the followed period.

Results

HBsAg levels at baseline ranged from ?1.4 to 5.32 log IU/ml, with a median value of 3.2 log IU/ml. Lower HBsAg levels were significantly associated with higher age and lower HBV replication status. The rate of change of HBsAg levels showed two peaks, with a cut-off value of ?0.4 log IU/year. Based on this, patients were tentatively classified into rapid decrease (rate of change P?=?0.028) lower in the rapid decrease group than in the non-rapid decrease group.

Conclusions

Lower baseline HBsAg levels were significantly associated with older age and lower viral activity. Both a loss of HBeAg detection as well as inactive replication of HBV are suggested to be fundamental factors contributing to a rapid decrease in HBsAg over the natural course of HBV infection.     

Hepatitis C viremia interferes with serum hepatitis B virus surface antigen and DNA levels in hepatitis B uremics

Purpose

Hepatitis B virus (HBV) and HCV might cause reciprocal interference. We aimed to elucidate the influence of HCV and interleukin-28B (IL-28B) genetic variants in the HBV DNA and HBsAg levels in uremic HBV carriers.

Methods

Assessment of HCV and HBV viral loads, HBsAg levels and IL-28B genotype were performed in 229 HBsAg-positive patients from a cohort of 1,681 uremics.

Results

Patients with HCV viremia had significantly lower HBV DNA (2.58 ± 0.80 vs. 3.16 ± 1.48 log IU/mL, p = 0.005) and HBsAg levels (1.33 ± 1.35 vs. 2.23 ± 1.31 log IU/mL, p = 0.002) compared with those without. IL-28B rs8099917 genotype had no impact on HBsAg and HBV DNA levels. In multivariate regression analysis, HCV RNA levels had a more significant negative correlation with HBsAg levels [β ?0.905; 95 % confidence interval (CI) ?1.477, ?0.334; p = 0.002] than with HBV DNA levels (β ?0.586; 95 % CI ?1.206, 0.034; p = 0.06). The serum HBV DNA and HBsAg levels had a positive correlation (r = 0.43, p < 0.001) among the 215 HBeAg-negative patients. However, the correlation was not observed in patients with HCV viremia (r = 0.23, p = 0.29). Linear regression analysis revealed that age (β ?0.286; 95 % CI ?0.043, ?0.014; p < 0.001) and the HBV DNA level (β 0.373; 95 % CI 0.239, 0.549; p < 0.001) correlated independently with the HBsAg level among HBeAg-negative patients without HCV viremia, but not among those with concomitant HCV viremia.

Conclusions

HCV viremia suppressed both HBsAg and HBV DNA levels. The HBsAg levels correlated with the HBV DNA levels only in patients without concomitant HCV viremia.     

Clinical significance and evolution of hepatic HBsAg expression in HBeAg-positive patients receiving interferon therapy

Background

Serum hepatitis B surface antigen (HBsAg) level is important in the management of chronic hepatitis B (CHB). However, it is unclear whether serum HBsAg reflects its expression in liver and the hepatic HBsAg evolution following interferon therapy.

Methods

Forty-five HBeAg-positive CHB patients receiving interferon-based therapy within a randomized, controlled, multicenter study during 1998–1999 were included. The hepatic HBsAg expressions were categorized into cytoplasmic, inclusion, marginal and negative patterns by immunohistochemical staining. The HBsAg-positive hepatocytes were quantified by image-based cytometry and correlated to HBV serological and virological profiles for clinical implications. The evolution of hepatic HBsAg levels was analyzed among 22 patients with paired liver biopsies before and after interferon therapy, sequentially.

Results

There was a positive correlation between pretreatment serum HBsAg and hepatic HBsAg levels (r = 0.67, P < 0.0001). The hepatic HBsAg expression pattern significantly evolved from cytoplasmic/inclusion pattern to marginal/negative pattern after interferon treatment. The serum HBV-DNA, HBsAg and hepatic HBsAg levels all decreased significantly after interferon therapy. Among 36 % patients with HBeAg loss after therapy, pretreatment hepatic HBsAg levels were significantly lower compared with those without HBeAg loss. After multivariate analysis, low pretreatment hepatic HBsAg levels rather than serum HBsAg titers were associated with a higher rate of HBeAg loss (OR: 4.97, 95 % CI: 1.12–22.00, P = 0.035).

Conclusions

The serum HBsAg level positively reflects the HBsAg level in liver which evolves significantly after interferon therapy. A lower hepatic HBsAg level is associated with HBeAg loss after interferon treatment. Hepatic HBsAg may have clinical significance in CHB patients receiving interferon treatment.     

Role of serum dehydroepiandrosterone sulfate level on the clearance of chronic hepatitis B virus infection

Background

The natural course of chronic hepatitis B virus (HBV) infection and relevant host factors remain unclear. This study aims to investigate the impact of dehydroepiandrosterone sulfate (DHEAS) on the clearance of chronic HBV infection.

Methods

Two hundred and one hepatitis B e antigen (HBeAg)-positive chronic HBV-infected children (101 females) were recruited. Serum DHEAS levels were determined in all subjects at 15 years of age. Serum alanine aminotransferase (ALT) levels, DHEAS levels, HBV seromarkers, genotypes, and viral loads were included for analysis.

Results

Subjects with serum DHEAS levels >3.6 μmol/L at midpuberty had earlier HBeAg seroconversion (median age, 14.7 vs. 18.2 years; HR, 1.9; P = 0.03), and the impact persisted even after adjusting for gender, HBV genotype, peak ALT levels, and viral load. Subjects with DHEAS levels >3.6 μmol/L at 15 years of age had more HBV viral titers decrement from 15 to 20 years of age (mean ± SD, 3.5 ± 2.5 vs. 1.2 ± 2.2 log10 copies/mL; P = 0.05) and shorter duration for HBeAg seroconversion than others (mean ± SD, 5.6 ± 4.4 vs. 9.2 ± 4.9 years; P = 0.02). Higher serum DHEAS levels at 15 years of age are also associated with greater hepatitis B surface antigen (HBsAg) titer decrement from 15 to 20 years of age (correlation coefficient = 0.45, P = 0.04).

Conclusions

Higher serum DHEAS levels at midpuberty predicts more HBV viral load and HBsAg titer decrement from midpuberty to young adulthood. Higher serum DHEAS levels at midpuberty also correlate with younger age of spontaneous HBeAg seroconversion in chronic genotype B and C HBV-infected patients.     

Anti-HBs response to hepatitis B immunoglobulin prophylaxis in liver transplant recipients

Background

Hepatitis B virus (HBV) recurrence after a liver transplant (LT) is a global issue. Several strategies have been adopted to prevent this recurrence. Most strategies recommend a combination of hepatitis B immunoglobulin (HBIG) and or nucleos(t)ide analogue.

Aim of the Study

The aim of the study is to determine the anti-HBs response to HBIG among Indian patients who had undetectable pre-transplant HBV DNA.

Methods

Seven adult HBV-related LT recipients of Indian origin with low pre-transplant HBV titres who had a liver transplant between August 2009 and June 2012 were included in the study. The protocol followed for post-liver transplant HBIG dose was titrated to achieve an anti-HBs titre of at least 100 IU/L. All recipients were on entecavir. Anti-HBs titre, and HBsAg status was checked at regular intervals. A retrospective analysis of the anti-HBs response to a loading and maintenance dose of HBIG was done.

Results

Seven adult HBV-related LT recipients on post-transplant prophylaxis with HBIG and nucleoside analogue (entecavir) fulfilled the criteria for the study. The median anti-HBs response to the anhepatic and loading dose of HBIG was high at 555 IU/L. In two, the response was less than 100 IU/L. The median dose of HBIG reduced at end of 1 month to 800 IU, and the median titre was 223 IU/L. For the next 11 months, the median requirement of HBIG was 3,000 and 4,000 IU, and the titre was low at 53.8 and 60.9 IU/L at end of 6 and 12 months, respectively.

Conclusions

The anti-HBs response to HBIG was variable, and titres even below 100 IU/L did not result in HBV recurrence when HBIG was given in combination with entecavir.     

Hepatitis B surface antigen levels: association with 5-year response to peginterferon alfa-2a in hepatitis B e-antigen-negative patients

Purpose

To investigate the durability of response to peginterferon alfa-2a up to 5 years post-treatment and factors associated with response in hepatitis B e-antigen (HBeAg)-negative patients.

Methods

HBeAg-negative patients received peginterferon alfa-2a (180 μg/week) ± lamivudine (100 mg/day) for 48 weeks as part of a multicenter, randomized study. The planned 5-year efficacy analysis included patients (n = 230) enrolled in the long-term follow-up study. On-treatment hepatitis B surface antigen (HBsAg) decline kinetics were analyzed retrospectively in a subgroup of patients with HBsAg data available at baseline, weeks 12, 24, and 48 on-treatment, and 6 months post-treatment (n = 120). Receiver operating characteristic analyses identified the on-treatment HBsAg levels associated with response at 1 and 5 years post-treatment.

Results

HBV DNA ≤2,000 IU/mL and HBsAg clearance at 5 years post-treatment were achieved by 23 and 12% of patients, respectively. High rates of HBsAg clearance at 5 years post-treatment were achieved by patients with HBV DNA ≤2,000 IU/mL at 1 year post-treatment (28%). Rates of HBV DNA ≤2,000 IU/mL at 1 year post-treatment were 47.2 and 43.4% in patients with ≥10% decline from baseline at weeks 12 and 24, respectively, compared with 16.4% (p = 0.0003) and 13.2% (p < 0.0004) in patients with a <10% decline. Rates of HBsAg clearance at 5 years post-treatment were 22.6 and 22.4% in patients with ≥10% decline at weeks 12 and 24, respectively, compared with 7.5% (p = 0.0161) and 3.8% (p < 0.0001) in patients with <10% decline.

Conclusions

Peginterferon alfa-2a results in increasing rates of HBsAg clearance during post-treatment follow-up in HBeAg-negative patients. On-treatment decline in HBsAg is significantly associated with long-term post-treatment response.     

Serum HBV RNA and HBeAg are useful markers for the safe discontinuation of nucleotide analogue treatments in chronic hepatitis B patients

Background

Treatment for chronic hepatitis B has improved drastically with the use of nucleot(s)ide analogues (NAs). However, NA therapy typically fails to eliminate Hepatitis B virus (HBV) completely, and it is difficult to discontinue these therapies. We previously demonstrated that NA therapy induced immature viral particles, including HBV RNA in sera of chronic hepatitis B patients. In the study reported here, we analyzed the association between HBV RNA titer and the recurrence rate of hepatitis after discontinuation of NA therapy.

Methods

The study cohort comprised 36 patients who had discontinued NA therapy. Serum HBV DNA or DNA plus RNA levels were measured by real time PCR and statistical analyses were performed using clinical data and HBV markers.

Results

At 24 weeks after discontinuation of NA therapy, HBV DNA rebound was observed in 19 of the 36 patients (52.8 %), and alanine aminotransferase (ALT) rebound was observed in 12 of 36 patients (33.3 %). Multivariate statistical analysis was used to identify factors predictive of HBV DNA rebound. The HBV DNA + RNA titer following 3 months of treatment was significantly associated with HBV DNA rebound [P = 0.043, odds ratio (OR) 9.474, 95 % confidence interval (CI) 1.069–83.957)]. Absence of hepatitis B e antigen (HBeAg) at the end of treatment was significantly associated with ALT rebound (P = 0.003, OR 13.500, 95 % CI 2.473–73.705). In HBeAg-positive patients, the HBV DNA + RNA titer after 3 months of treatment was marginally associated with ALT rebound (P = 0.050, OR 8.032, 95 % CI 0.997–64.683).

Conclusions

Monitoring of serum HBV DNA + RNA levels may be a useful method for predicting re-activation of chronic hepatitis B after discontinuation of NA therapy.     

Clearance of hepatitis B surface antigen during long-term nucleot(s)ide analog treatment in chronic hepatitis B: results from a nine-year longitudinal study

Background

Clearance of hepatitis B surface antigen (HBsAg) is considered the ultimate goal in chronic hepatitis B treatment. One treatment option is long-term nucleot(s)ide analog (NA) therapy. We followed a group of long-term NA therapy patients to evaluate the efficacy of this treatment in promoting clearance and longitudinal declines of HBsAg.

Method

The study included 791 NA therapy patients who received lamivudine as their first drug. At the baseline, 442 patients were hepatitis B e antigen (HBeAg)+ and 349 were HBeAg?. All analyses were performed after separating the HBeAg+ and HBeAg? cohorts. Cox proportional hazards models were used to determine which factors were associated with HBsAg clearance.

Results

HBsAg clearance was observed in 18 (4.1 %) of the HBeAg+ patients and 20 (5.7 %) of the HBeAg? patients at baseline, giving seroclearance rates of 6.4 and 6.9 %, respectively, over the nine-year study period. HBsAg clearance was influenced by several independent factors that varied according to HBeAg cohort. For HBeAg+ patients, these included previous interferon therapy, infection with hepatitis B virus (HBV) genotype A, a ≥0.5 log IU/mL decline in HBsAg level within six months, and clearance of HBeAg at six months. For HBeAg? patients, these included infection with HBV genotype A, decline in HBsAg at six months, and a baseline HBsAg level of <730 IU/mL.

Conclusion

This study suggests that both direct antiviral potential and host immune response are needed to achieve HBsAg clearance by NA therapy. Viral genotype strongly influenced HBsAg clearance during NA therapy.     

Serum hepatitis B virus DNA before liver transplantation correlates with HBV reinfection rate even under successful low-dose hepatitis B immunoglobulin prophylaxis

Purpose

The combination of hepatitis B immunoglobulin (HBIg) and nucleos(t)ide analogues has been accepted as the best treatment to control hepatitis B recurrence after orthotopic liver transplantation (OLT). However, the optimal dose of HBIg remains unclear. We have previously reported that high-dose HBIg in the early period followed by low-dose HBIg with nucleos(t)ide analogues offers reliable and cost-effective control of hepatitis B recurrence. The aim of this study was to investigate intrahepatic hepatitis B virus (HBV) reinfection status with our clinically successful protocol.

Methods

We quantified levels of intrahepatic HBV covalently closed circular (ccc) deoxyribonucleic acid (DNA) and serum hepatitis B core-related antigen (HBcrAg), a new serological marker that can estimate intrahepatic cccDNA levels. Nucleos(t)ide analogues were administered in all cases.

Results

No patients showed recurrence of hepatitis B surface antigen (HBsAg) or HBV-DNA. However, HBV, cccDNA, and HBcrAg were positive in 57% and 48% of patients after OLT, respectively. Pre-OLT serum HBV-DNA and HBcrAg levels correlated linearly with post-OLT cccDNA levels (r = 0.534, P < 0.05, and r = 0.634, P < 0.05, respectively). High serum HBV-DNA and HBcrAg levels, particularly with >3 log₁₀ copies/mL and >4 log₁₀ IU/mL, respectively, at the time of OLT, were associated with high levels of post-OLT cccDNA. Even with our successful protocol, nearly half of patients showed HBV reinfection.

Conclusions

Patients with high serum HBV-DNA and HBcrAg levels before OLT (particularly >3 log₁₀ copies/mL and >4 log₁₀ IU/mL, respectively) should be followed with care for HBV recurrence.     

Relationship between age and prevalence of hepatitis B infection in first-year university students in Hong Kong

Purpose

To determine the effect of age on the prevalence of hepatitis B virus (HBV) infection during a routine screening programme of first-year students enrolled in Health Sciences Studies at the Chinese University of Hong Kong from 2001 to 2009.

Methods

In a retrospective cohort study, data on the hepatitis B surface antigen (HBsAg) status was retrieved from the University Health Service and analysed according to the age of the student at testing and year of birth.

Results

Of the 2,688 students enrolled in the study group, 79 (2.9 %) tested positive for HBsAg. The prevalence increased significantly from 0.9, 2.3, 4.3 to 5.5 % for those tested at age ≤18, 19, 20 and ≥ 21 years, respectively (p < 0.001). On logistic regression analysis, taking age ≤18 years and year of birth before 1983 (before the availability of HBV vaccination) as the reference group, HBV infection increased progressively with age, with an adjusted odds ratio of 3.36 [95 % confidence interval (CI) 1.01–11.23], 6.04 (95 % CI 1.74–20.98) and 11.61 (95 % CI 3.20–42.13) for age 19, 20 and ≥21 years, respectively. There was no significant change in the odds ratio after adjustment for the year of birth before and after introduction of the vaccination programme.

Conclusion

Among the university students enrolled in our study, the overall prevalence of HBV infection before and after the introduction of HBV vaccination was lower than the 10 % found in the general population. There was, however, a significant progressive increase with age at testing from ≤18 to ≥21 years, suggesting a previously overlooked contribution of horizontal transmission to the high prevalence of HBV infection found in our adult population.